Taking exenatide (Byetta, Bydureon) with rosiglitazone (Avandia) may diminish the cardiovascular risks associated with the latter by moderating its effects on blood clotting, according to a database study.

By looking at data from the FDA's Adverse Event Reporting System (AERS), Ravi Iyengar, PhD, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues found that there were fewer reports of MI among patients taking rosiglitazone and exenatide together compared with those on rosiglitazone alone (2% versus 34%).

The researchers then turned to a systems biology network to find potential mechanisms behind the interaction, hypothesizing that effects on plasminogen activator inhibitor-1 (PAI-1), a known predictor of clot risk, may be involved. And a diabetic mouse model seemed to confirm those effects, they reported in Science Translational Medicine.

Iyengar cautioned that clinical studies are needed before making any recommendations about co-prescribing the two drugs, but he noted that the methodology can be used to find other positive drug-drug interactions.

"Many times when people take two drugs, they have unanticipated beneficial effects, and when things go well, no one complains," Iyengar told MedPage Today. "So these beneficial effects typically go unnoticed, and it's the data-mining of these big databases that allows us to see them."

Iyengar and colleagues searched the AERS database for an interaction that might mitigate the risks associated with rosiglitazone. They found that the combination of rosiglitazone plus exenatide was associated with a significantly lower proportion of MI reports compared with rosiglitazone monotherapy (OR 0.04, 95% CI 0.03 to 0.05, P<0.001).

Clinical data from a Mount Sinai dataset supported those observations from AERS, they noted.

Next, the researchers looked for molecular mechanisms by which exenatide could protect against rosiglitazone's adverse cardiac effects. They used a systems biology approach by searching cell biological networks from interaction databases, which Iyengar says are "not so different from a social network, except this applies to chemical reactions."

These searches turned up a significant relationship for a clotting regulation network (P=0.016) -- specifically, that PAI-1 may play a role in the interaction between exenatide and rosiglitazone.

"Since rosiglitazone is associated with both an increased risk of MI and stroke, it is reasonable to think this may be related to changing of clotting dynamics," Iyengar told MedPage Today.

They tested the hypothesis in a mouse model and found that treatment with rosiglitazone resulted in a 74% increase in PAI-1 levels in diabetic animals compared with diabetic mice that weren't treated (P<0.01), while there were no significant effects of exenatide alone.

When the drugs were combined, however, treated and untreated diabetic mice had similar levels of PAI-1 (P<0.001), suggesting exenatide prevents the rise in PAI-1 seen with rosiglitazone alone. And several measures of clotting were worsened with rosiglitazone alone but mitigated by the therapeutic combination, they reported.

Iyengar and colleagues mined the AERS data for other potential interactions and found 19,133 combinations of beneficial drug-drug interactions that could be further studied, including treatments for anaphylactic shock and suicide.

They cautioned about the limitation of AERS data, but concluded that "combining statistical models of drug interactions from AERS with cell biological interaction-based subnetwork construction can lead to generation of unbiased hypotheses for mechanisms of action."

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